Compared with cultured diploid hippocampal neurons, neurons from fetal trisomy 16 mouse (Ts16), a model for Down syndrome (DS), showed a decreased the voltage-dependent sodium current during activation, as well as fewer sodium channels assessed by binding of radiolabeled saxitoxin. mRNAs encoding the alpha and beta1 subunits of the sodium channels were not altered, indicating post-transcriptional dysregulation in channel formation. High-voltage-activated calcium currents were larger in Ts16 neurons compared to controls. Ts16 neurons, correspondingly, bound more L-type calcium ligand, although mRNAs for channel subunits were normal. Thus, mental retardation in Down syndrome may be an ion channel dysfunction. The ultrastructural morphology of fetal Ts16 and diploid hippocampus and dorsal root ganglion did not differ, consistent with this interpretation. Cultured Ts16 Dorsal root ganglion (DRG) neurons were less able to adhere to laminin-coated dishes than diploid neurons. Differences depended on nerve growth factor (NGF). Septal neurons from the brain are NGF-dependent. In primary culture, a subpopulation of highly excitable Ts16 septal neurons had bigger inward currents during the action potential than highly excitable diploid septal neurons.